The broad objective of this Program Project is a better understanding of the physiological, biochemical, and molecular processes involved in the reactions of the cardiovascular and skeletal muscle systems to exercise. A principal function of any animal is the conversion of chemical energy to mechanical work. Thus, our primary goal is to study quantitatively the mechanisms that regulate and limit the energy utilization of the body during exercise. Experiments will be performed on the acute response and chronic adaptation to exercise. Well-established methods of muscle biochemistry, cardiovascular, and neural physiology, as well as newer techniques of gene transfer will be utilized in these studies. Currently, experiments are being conducted at multiple levels including the integrated acute response and chronic adaptation to dynamic and static exercise in animals and in human subjects and patients. However, a fundamental understanding of the total body response to exercise is dependent upon a better appreciation of the regulatory mechanisms involved in skeletal muscle contraction and in energy utilization and of the regulatory mechanisms involved in organ and system function. Therefore, experiments are being performed in anesthetized animals, isolated organs, cells, and in vitro reconstitution systems. Such a broad attack directed at all the regulatory mechanisms (molecular, cellular, organ, system, and whole body) involved in the response and adaptation to exercise should provide (1) a better understanding of the determinants of human physical performance, (2) a more logical basis for classification and quantitation of disorders affecting the cardiovascular and skeletal muscle systems, and (3) a more rational therapeutic approach to diseases of these systems. Close contact and cooperation between the members of the group primarily concerned with clinical research and integrative biology, and those who are working in the basic science areas of biochemistry, cell biology, physiology, and molecular biology have provided the background considered essential for the success of this program during the past 40 years. These close collaborations will continue to be an excellent environment for advancements in our understanding of the regulatory mechanisms involved in the response and adaptation to exercise.